Ten-eleven Translocation (TET)
Alfa Cytology specializes in the development of novel therapeutic agents for leukemia therapy. Our dedicated team of experts is committed to advancing the field of epigenetic drug by focusing on the development of (ten-eleven translocation) TET inhibitors. TET proteins play a crucial role in DNA demethylation and have emerged as promising targets for the therapy of leukemia and other hematological malignancies.
Introduction to TET Dioxygenases in Leukemia
The enzymatic activities of TET proteins, namely TET1, TET2, and TET3, facilitate the conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), thereby facilitating the process of DNA demethylation. As effective targeted therapeutic approaches for malignancies with TET2 mutations are currently lacking, research efforts are underway to investigate the inhibitory effects of TET inhibitors on AML and CML. TET inhibitors hold promising potential as a novel class of targeted drugs for TET2-mutated in leukemia.
Fig. 1. OPA1-induced activation of OPRM1 signaling enhances the transcription of TET2 in leukemia. (Zhao, H. et al., 2022)
Novel Therapeutic Strategy Targeting TET Proteins
In leukemia, the TET1 and TET2 members of the TET family are crucial oncogenic proteins involved in leukemia progression. Therefore, TET1 and TET2 represent two attractive therapeutic targets for leukemia. We provide distinct development strategies for TET inhibitors targeting these two proteins.
- TET1
- TET2
- STAT/TET1 axis
Discovery of TET Inhibitors for Leukemia
We offer various methods for screening TET inhibitors for leukemia. These methods encompass the use of conventional pharmacological tools such as in vivo and in vitro models, as well as the development and testing of pharmacological hypotheses using computational approaches.
| Methods | Service Details |
|---|---|
| Cell-based screening | To assist our clients in discovering novel TET inhibitors, we have dedicated efforts to developing leukemia cell lines and establishing an in vitro TET agonist screening system for drug screening purposes. |
| In silico pharmacology | We utilize computational methods and tools to design and synthesize candidate compounds for our clients. This design and synthesis process is based on the αKG binding site within the catalytic domain of TET2, aiming to identify small molecule inhibitors that can effectively inhibit the residual DNA dioxygenase activity. |
Validation and Identification of TET Inhibitors
Enzyme Activity Assays for TET Inhibitors
We offer a comprehensive range of in vitro assays to evaluate the inhibitory activity of TET inhibitors. These assays include enzymatic activity assays, kinetic studies, and analyses of TET-mediated DNA demethylation. Our assays provide quantitative data on the potency and mechanism of action of the inhibitors.
Cellular Assays for Anti-Leukemic Activity
We employ leukemia cell lines and patient-derived primary cells to assess the impact of TET inhibitors on cellular growth, differentiation, and apoptosis. Our assays measure the effects of the inhibitors on DNA demethylation, gene expression profiles, and epigenetic reprogramming in leukemia cells.
In Vivo Efficacy Studies
Utilizing leukemia animal models, including xenograft models and genetically modified leukemia models, we conduct in vivo efficacy studies to evaluate the therapeutic potential of TET inhibitors. These studies provide valuable insights into the inhibitors' impact on leukemia progression, tumor burden, and overall survival.
Pharmacokinetic and Safety Profiles
Our team evaluates the pharmacokinetic properties of TET inhibitors, including absorption, distribution, metabolism, and excretion (ADME), to ensure proper dosing and optimal drug exposure. Additionally, we assess the safety and toxicity profiles of the inhibitors through rigorous preclinical studies.
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Alfa Cytology is a renowned international company that provides innovative solutions in the field of life science. Collaborate with us in the development of TET inhibitors for leukemia and unlock the potential of epigenetic therapies in hematological malignancies. Contact us to discuss your project requirements.
Reference
- Zhao, H.; et al. Opioid receptor signaling suppresses leukemia through both catalytic and non-catalytic functions of TET2. Cell Reports. 2022, 38(4): 110253.